While solid tumors occur in organs, liquid tumors consist of blood cells that have become cancerous. Tumors express proteins in patterns not found in normal cells. The pattern of proteins exhibited by tumor or malignant cells can reflect the stage of disease (i.e., early stage or metastatic disease). As a malignancy progresses, the cells tend to differ more and more from the tissue from which they originated. As a cancer progresses becoming more undifferentiated, regardless of the staging schema used to determine the cancer's progression, the cells become more likely to metastasize and/or are more refractory to treatment by traditional therapies. Leukemias and myelomas are among the most common blood cancers.
Integrins are a family of cell-surface glycoproteins involved in cell-adhesion, immune cell migration and activation. Alpha-4 integrin is expressed by all circulating leukocytes except neutrophils, and forms heterodimeric receptors in conjunction with either the beta-1 (β1) or beta-7 (β7) integrin subunits. Both alpha-4beta-1 (α4β1) integrin and alpha-4beta-7 (α4β7) integrin play a role in migration of leukocytes across the vascular endothelium (Springer et al., Cell, 1994, 76: 301-14; Butcher et al., Science, 1996, 272: 60-6) and contribute to cell activation and survival within the parenchyma (Damle et al., J. Immunol., 1993; 151: 2368-79; Koopman et al., J. Immunol., 1994, 152: 3760-7; Leussink et al., Acta Neuropathol., 2002, 103: 131-136). Alpha-4beta-1 integrin is constitutively expressed on lymphocytes, monocytes, macrophages, mast cells, basophils, and eosinophils.
Alpha-4beta-7 (also known as very late antigen-4, VLA-4), binds to vascular cell adhesion molecule-1 (VCAM-1) (Lobb et al., J. Clin. Invest. 1994, 94: 1722-8), which is expressed by the vascular endothelium at many sites of chronic inflammation (Bevilacqua et al., 1993, Annu. Rev. Immunol., 11: 767-804; Postigo et al., 1993, Res. Immunol., 144: 723-35). Alpha-4beta-1 integrin has other ligands, including fibronectin and other extracellular matrix (ECM) components.
Alpha-4beta-7 integrin interacts with mucosal addressin cell adhesion molecule (MAdCAM-1), and mediates homing of lymphocytes to the gut (Farstad et al., 1997, Am. J. Pathol., 150: 187-99; Issekutz, 1991, J. Immunol. 147: 4178-84). The alpha unit is the most important in binding actions within the alpha4 set. Accordingly, anti-alpha-4 intregrin agents may have activity despite being mixed inhibitors of alpha4beta1 and alpha4beta7. Further, it has been found that the disruption of alpha-4 integrin-mediated call adhesion restores drug sensitivities. Anti-alpha-4 treatment with chemotherapeutic agents, such as melphalan, is more effective against myeloma than a single agent treatment. Alpha-4 interaction with VCAM-1 or fibronectin promotes resistance to fludarabine. Alpha-4beta-1-fibronectin interaction promotes chemoresistance of acute myelogenous leukemia (AML) cells lines.
Many hematological tumors, such as leukemia, myeloma, and melanoma, may be positive for alpha-4 integrins. Accordingly, the growth and survival of these tumors depends on interaction with alpha-4 integrin. Metastatic tumors express VCAM-1. It has been seen that anti-alpha-4 treatment decreased bone destruction and increased apoptosis of myeloma cells in the bone marrow compartment. Alpha-4 interaction with VCAM-1 or fibronectin promotes survival of patient derived chronic lymphoblastic leukemia (CLL) cells. Alpha-4beta-1-fibronectin interaction has been seen to promote survival of AML cells lines in vitro.
Alpha-9 integrins play a role in development of lymphatics, granulocytes, osteoclasts and angiogenesis. Alpha-9 plays a role in lymphangiogenic growth, probably through VEGFC and/or VEGFA binding (which mediates vascular growth and angiogenesis). Alpha-9 integrin also affects granulocytes, the development of osteoclasts, and neutrophils. Alpha-9 has been shown to accelerate cell migration in vitro.
In alpha-9 knock out mice, there is a dramatic defect specific for neutophils. Knock downs of Kir4.2 inhibits alpha-9 mediated cell migration of microvascular endothelial cells. Further, there is reduced G-CSF induced colony formation in alpha-9 deficient bone marrow cells. Accordingly, there are strong implications for the use of anti-alpha-9 agents in the treatment of cancers.
Of the alpha-9 integrins, alpha-9beta-1 is most closely homologous to alpha-4 beta-1. Alpha-9beta-1 recognizes growth factor receptors, e.g., VEGFC (lymphangiogenesis) as well as VEGFA (vascular growth mediator). Alpha-9beta-1 integrin is expressed on microvascular endothelial cells and interacts with thrombospondin-1. This interaction is involved in modulation of angiogenesis. Alpha-9beta-1 directly binds to VEGF-C and D and contributes to lymphangiogenesis. Thus, the integrin alpha-9beta-1 as a potential pharmacotherapeutic target for inhibition of pathogenic angiogenesis and lymphangiogenesis.
Alpha-9 integrins have been shown to have activity in relation to solid tumors. For example, Basora et al. report the expression of alpha-9beta-1 integrin in human colonic epithelial cells in subsets of colon cancer (Int J Cancer. 1998 Mar. 2; 75(5): 738). Häkkinen et al. report the expression of alpha-9 integrin in oral leukoplakia, lichen planus and squamous cell carcinoma. (Oral Dis. 1999 July; 5(3): 210-7) Tomczuk et al. report the activity of multiple beta-1 integrins in cell adhesion to the disintegrin domain of ADAMs 2 and 3. (Exp Cell Res. 2003 Oct. 15; 290(1): 68-81). Chen et al. showed that mice lacking alpha-9beta-1 have a dramatic reduction in neutrophil development and numbers. (Immunity, 2006, 17137800).
However, new agents, compositions and methods for using these agents and compositions that inhibit growth and metastasis of liquid tumors are needed, which can be used alone or in concert with other agents.